In addition to the well documented effects of estrogen on reproductive tissue, bone and cholesterol metabolism in post-menopausal women, it is known that estrogen has a number of actions in the central nervous system with both somatic and behavioral consequences.
In climacteric women, anxiety, depression, tension and irritability begin during the perimenopause and can be a correlated to reduced estrogen levels. Estrogen replacement therapy has been recommended for the treatment of these symptoms (cf. J. Malleson, Lancet, 2: 158 (1953) and R. Wilson, et al., J. Am. Geriatric Soc., 11:347 (1963)).
The mechanism for the protective effects of estrogen against depression and mood swings is not well understood, but may be related to the potential effects of estrogen on biogenic amines such as serotonin (cf. M. Aylward, Int. Res. Communications System Med. Sci., 1: 30 (1973).
In the area of memory and cognition enhancement, S. Phillips, et al., Psychoneuroendocrinology, 17: 485-495 (1992) have reported that in surgically menopausal women given estrogen, scores in immediate and delayed recall tests are greater than in similar women not given estrogen. In a prospective cohort study in post-menopausal women, A. H. Paganini-Hill, et al., Am. J. Epidemiol., 140(3): 256-261 (1994) demonstrated that the risk of Alzheimer's disease was less in estrogen users as compared with women who did not use estrogen. Furthermore, the risk of Alzheimer's disease decreased significantly with increasing doses of estrogen and increased duration of estrogen use.
All of the these studies have lead to the growing perception in the literature that estrogen replacement therapy is a promising treatment for central nervous system disorders such as depression and mood swings and of Alzheimer's disease in post-menopausal women. These promising uses of estrogen replacement therapy are off-set, however, by the disadvantages of long-term estrogen therapy associated with the risks of developing reproductive tissue cancers.
Women on estrogen replacement therapy develop endometrial cancer at rates three to six times higher than nonusers after three to six years of use; after ten years on estrogen replacement therapy, the risk ratio increases to tenfold. A growing body of literature suggests that long-term (i.e. 10-15 years) causes a thirty to fifty percent increase in the risk of breast cancer.
Thus, there is a need for the development of compounds which are alternatives to estrogen possessing the same beneficial effects on depression and mood swings and on the treatment of Alzheimer's disease, but which lack the detrimental effects on reproductive tissue.